In most eukaryotic cells, G1 phase is the primary interval for integration of internal and environmental signals with the cell cycle apparatus. Failure to respond to those signals can lead to defects in proliferation that, in metazoans, may include malignancy and even death. One of the primary controls governing cell cycle progression is via coordinate regulation of a large family of G1-specific genes. Genes of that family encode numerous cell cycle regulators including G1 and S phase cyclins that promote progression through early stages of the cell cycle. Consequently, modulating expression of G1-specific genes is an efficient way of coordinately regulating many processes. In yeast, the G1-specific transcription program is activated by the G1 cyclin-associated cyclin dependent protein kinase, CIn3/CDK that activates promoter-associated SBF and MBF transcription factors via an unknown mechanism. The goal of the proposed research is understand the regulation G1-specific gene expression and the integration of transcriptional regulation with the cyclin/CDK machinery. This will be accomplished through discovery and characterization of novel regulators of SBF and MBF and by understanding the interaction of CIn/CDK with regulators of transcription.
In Specific Aims 1 and 2, we propose to further characterize Whi5, which we recently described as negative regulator of SBF-dependent transcription antagonized by CIn3/CDK.
In Specific Aim 3, we propose to identify and characterize novel regulators of SBF and MBF. Finally, in Specific Aim 4, we propose to establish the biological relevance of the interaction between the RSC chromatin-remodeling complex and G1 cyclins. We are hopeful that completion of the proposed research will provide a broad understanding of coordination of the cell cycle regulatory apparatus with the transcriptional machinery, thereby, enhancing our understanding of the control of cell proliferation in both normal and disease states. ? ?
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